Acute Myeloid Leukemia (AML) is a broad range of disorders that all have the defining feature of leukemic cells with a maturation arrest. Despite the fact that AML is the most common form of leukemia in adults, there have been no changes in standard therapy in over 40 years. The traditional chemotherapeutics used exhibit both high toxicity and poor efficacy with a median survival in patients over the age of 56 of less than one year with only 20% of these patients surviving two years. Instead of directly cytotoxic agents, agents that induce the maturation of AML cells offers a therapeutic approach that targets the primary pathophysiology of the disease. We previously identified a plant derived alkaloid as a promising AML differentiation agent. Our lead compound exhibits high potency on AML cells and promising activity in a mouse model of human AML. Mechanistic studies suggest that this agent leads to perturbation of mitochondrial metabolism through inhibition of the enzyme thioredoxin reductase. In this proposal we propose to develop our lead compound by identifying ideal routes and schedules of dosing to mice, confirming the activity and mechanism of action of our lead compound in mouse models of human AML and identifying the optimal AML patients for this therapy. It is hoped that this work will lead to a more efficacious and safer therapy for AML patients.